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Tears Yield Possible MS Biomarker

The tears of MS patients contain high levels of an inflammation-inhibiting protein that might serve as a diagnostic biomarker for MS

Jennie Dusheck, M.A.

MS presents with a wide variety of symptoms, making accurate diagnosis difficult and requiring detailed clinical examination, expensive MRI imaging, and invasive lumbar punctures. A safe and simple biomarker would be easier on both patients and doctors and possibly enable earlier diagnosis.

Cindy Salvisberg and colleagues at the Medical University Center of the University of Geneva, Switzerland, have uncovered a new MS biomarker that can be safely collected from patients’ tears. Their study appeared online ahead of print in Proteomics Clinical Applications (Salvisberg et al., 2014).

For the study, an ophthalmologist collected the tears of 30 MS patients and 25 control subjects by placing a glass capillary along the edge of the lower eyelid. Patients were kept as calm as possible and their eyes were not deliberately irritated, which is often done in other studies to stimulate a greater volume of tears. This was because the composition of tears can change with emotion and physical irritation.

The tears contained 185 different proteins. Of those, 42 proteins distinguished MS patients from controls. But only one protein—alpha-1 antichymotrypsin (serpin A3)—was consistently elevated in three different tests of MS patients’ tears. That same protein, serpin A3, was also found to be elevated in blood serum and cerebrospinal fluid, suggesting that a tear test might be substituted for the invasive lumbar puncture (spinal tap). Tear collection is easy, and the authors said the composition of tears reflects systemic and CNS health.

MS patients in Salvisberg’s study had relatively mild disease and their dates of diagnosis ranged from less than 1 year to 37 years earlier. The protein serpin A3 was elevated by 1.6 to 2.5 times the levels measured in controls. The elevation of serpin A3 seemed unrelated to age, sex, disease duration, or treatment with interferon β-1a.

Two other proteins found in the tears—zymogen granule protein 16 homolog B (ZG16B) and proline-rich protein 4 (PRR4)—were depressed in MS patients.

Changes in serpin A3 levels are associated with other major diseases, including cancer, chronic obstructive pulmonary disease, heart failure, atherosclerosis, aneurysms, and Alzheimer disease, raising questions about the specificity of the test.

The authors proposed that tears “may offer potentially new biomarkers for multiple sclerosis diagnosis, progression or therapeutic response.” Early diagnosis of MS opens the door to earlier treatment. And some biomarkers can help clinicians monitor disease progression and treatment efficacy.

Key open questions

Will these results be confirmed in a larger study?

Are the small volumes of tears sufficient for clinical diagnosis?

If serpin A3 is also found in serum, is there a reason to collect tears instead of blood?

Since serpin A3 may be elevated in other diseases, is it specific enough to make a useful diagnostic biomarker?

Would a larger study reveal changes in biomarker levels dependent on disease progression or treatment?

Comments

12 Feb 2014

Allan J. Tobin, CHDI Foundation

It’s a nice piece of work. It has some interesting suggestions. It shows that people are concerned with the right questions.

But in terms of the utility of this particular biomarker for diagnosis, the question is whether it has good sensitivity and specificity. The sensitivity might be great. But given that it’s elevated in other diseases, it’s likely that the specificity is not going to be great.

Biomarkers are used in three ways. Here they are talking about using the biomarker as a diagnostic marker. But biomarkers can also be used to track disease progression and the efficacy of a particular treatment. Serpin A3 may be useful for diagnosing the disease. But it doesn’t look like it’s going to be a useful biomarker in terms of tracking disease progression or tracking response to a drug, since the authors have already told us that there was no correlation between whether people were treated or not treated, how long they were sick, and so forth.

17 Feb 2014

Jagannadha Avasarala, Greenville Health System

It's too early to say if tears might yield proteins that could useful as biomarkers in MS.

Broadly, serpins are serine protease inhibitors and are involved in thrombosis, dementia, cancer metastasis and inflammation. Serpins undergo conformational changes (folding, etc, in 3 D) to inhibit proteases, and it follows that serpinopathies are diseases that arise possibly secondary to misfolding of serpins due to mutational changes - protein misfolding is probably a theme in the genesis of Alzheimer's and CJD. Serpin B1 upregulation was noted in B cells obtained from siblings with MS, compared to siblings who had no MS (J Avasarala, et al., BMC Medical Genomics, 2008, 1:2).

Issues of specificity, sensitivity, correlation to disease status/MRI findings and the onerous task of tear collection need to be sorted out first for tears to become the substrate of choice. From a scientific perspective, one would expect CSF to harbor the answers but any relatively non-invasive method to ID disease takes us closer to understanding the disease better.